The routine use of cross-sectional imaging has resulted in a significant increase in the age-adjusted incidence of renal cell carcinoma (RCC). However, this has not translated into a decrease in cancer specific deaths, suggesting the possible over treatment of small, potentially indolent renal tumors. Thus, active surveillance of RCC has been proposed for small tumors. However, the natural history of these tumors remains unknown. Angiogenesis and tumor necrosis correlate with prognosis and metastatic potential in RCC. Inactivation of the VHL gene, HIF upregulation, and VEGF over- expression form the molecular basis of the enhanced angiogenesis associated with RCC. Arterial spin labeling (ASL) is a magnetic resonance imaging (MRI) method for measuring blood flow by manipulating the signal from inflowing arterial blood. ASL blood flow correlates tightly to vascularity in RCC. The apparent diffusion coefficient (ADC) in RCC, measured with diffusion-weighted imaging (DWI), correlates with tumor cellularity at pathology. We seek to identify vascular and diffusion MRI measures in RCC in vivo that correlate to spatially-co-registered molecular alterations promoting angiogenesis and hypoxia and predict aggressive behavior. The spatial synchronization of various tissue-based analyses with in vivo alterations in tumor perfusion and hypoxia may help develop more robust imaging biomarkers to predict the biologic behavior of RCC. If successful, these imaging biomarkers will be immediately applicable to clinical practice and will help selecting patients for active surveillance. PUBLIC HEALTH RELEVANCE: The aim of the proposed research is to investigate the correlation between in vivo magnetic resonance imaging (MRI) measures of blood flow and cellularity with the molecular alterations that promote angiogenesis and necrosis in renal cell carcinoma (RCC) and to correlate these to the biologic behavior of these tumors. Quantitative measures of blood flow and cellularity will be obtained with arterial spin labeling (ASL) and diffusion weighted imaging (DWI), respectively.